Noncoding RNAs: Potential players in the self-renewal of mammalian spermatogonial stem cells.

Spermatogonial stem cells (SSCs), a unique population of male germ cells with self-renewal ability, are the foundation for maintenance of spermatogenesis throughout the life of the male. Although many regulatory molecules essential for SSC self-renewal have been identified, the fundamental mechanism underlying how SSCs acquire and maintain their self-renewal activity remains largely to be elucidated. In recent years, many types of noncoding RNAs (ncRNAs) have been suggested to regulate the SSC self-renewal through multiple ways, indicating ncRNAs play crucial roles in SSC self-renewal. In this paper, we mainly focus on four types of ncRNAs including microRNA, long ncRNA, piwi-interacting RNA, as well as circular RNAs, and reviewed their potential roles in SSC self-renewal that discovered recently to help us gain a better understanding of molecular mechanisms by which ncRNAs perform their function in regulating SSC self-renewal.

Functional role of the RET dependence receptor, GFRa co-receptors and ligands in the pituitary.

The RET receptor is a tyrosine kinase receptor implicated in kidney and neural development. In the adenopituitary RET and the co-receptor GFRa1 are expressed exclusively in the somatotrophs secreting GH. RET is implicated in a clever pathway to maintain at physiological levels the number of somatotrophs and the GH production. Thus, in absence of its ligand GDNF, RET induces apoptosis through massive expression of Pit-1 leading to p53 accumulation. In the presence of the ligand GDNF, RET activates its tyrosine kinase and promotes survival at the expense of reducing Pit-1 expression and downregulating GH. Recent data suggest that RET can also have a second role in pituitary plasticity through a second co-receptor GFRa2.

Glial cell line-derived neurotrophic factor family ligands enhance capsaicin-stimulated release of calcitonin gene-related peptide from sensory neurons.

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are a group of peptides that have been implicated as important factors in inflammation, since they are released in increased amounts during inflammation and induce thermal hyperalgesia upon injection. Mouse isolated sensory neurons in culture and freshly dissociated spinal cord slices were used to examine the enhancement in stimulated-release of the neuropeptide, calcitonin gene-related peptide (CGRP), as a measure of sensitization. Exposure of isolated sensory neurons in culture to GDNF, neurturin, and artemin enhanced the capsaicin-stimulated release of immunoreactive calcitonin gene-related peptide (iCGRP) two- to threefold, but did not increase potassium-stimulated release of iCGRP. A similar profile of sensitization was observed in freshly dissociated spinal cord slices. Persephin, another member of the GFL family thought to be important in development, was unable to induce an enhancement in the release of iCGRP. These results demonstrate that specific GFLs are important mediators affecting sensory neuronal sensitivity, likely through modulation of the capsaicin receptor. The sensitization of sensory neurons during inflammation, and the pain and neurogenic inflammation resulting from this sensitization, may be due in part to the effects of these selected GFLs.

Polymorphisms in the genes encoding the 4 RET ligands, GDNF, NTN, ARTN, PSPN, and susceptibility to Hirschsprung disease.

PURPOSE: Hirschsprung disease (HSCR) is a developmental disorder caused by a failure of neural crest cells to migrate, proliferate, and/or differentiate during the enteric nervous system development. It presents a multifactorial, nonmendelian pattern of inheritance, with several genes playing some role in its pathogenesis. Its major susceptibility gene is the RET protooncogene, which encodes a receptor tyrosine kinase activating several key signaling pathways in the enteric nervous system development. Given the pivotal role of RET in HSCR, the genes encoding their ligands (GDNF, NRTN, ARTN, and PSPN) are also good candidates for the disease. METHODS: We have performed a case-control study using Taqman technology to evaluate 10 polymorphisms within these genes, as well as haplotypes comprising them, as susceptibility factors for HSCR. RESULTS: No differences were found in the allelic frequencies of the variants or in the haplotype distribution between patients and controls. In addition, no particular association was detected of the variants/haplotypes to any demographic/clinical parameters within the group of patients. CONCLUSION: These data would be consistent with the lack of association between these polymorphisms and HSCR, although they do not permit to completely discard a possible role of other variants within these genes in the disease. Moreover, because the gene-by-gene approach does not take into account the polygenic nature of HSCR disease, it would be interesting to investigate sets of variants in many other different susceptibility loci described for HSCR, which may permit to consider possible interactions among susceptibility genes.

Postnatal roles of glial cell line-derived neurotrophic factor family members in nociceptors plasticity.

The neurotrophin and glial cell line-derived neurotrophic factor (GDNF) family of growth factors have been extensively studied because of their proven ability to regulate development of the peripheral nervous system. The neurotrophin family, which includes nerve growth factor (NGF), NT-3, NT4/5 and BDNF, is also known for its ability to regulate the function of adult sensory neurons. Until recently, little was known concerning the role of the GNDF-family (that includes GDNF, artemin, neurturin and persephin) in adult sensory neuron function. Here we describe recent data that indicates that the GDNF family can regulate sensory neuron function, that some of its members are elevated in inflammatory pain models and that application of these growth factors produces pain in vivo. Finally we discuss how these two families of growth factors may converge on a single membrane receptor, TRPV1, to produce long-lasting hyperalgesia.

The roles of glial cell line-derived neurotrophic factor, tumor necrosis factor-alpha, and an inducer of these factors in drug dependence.

There are few efficacious medications for drug dependence at present. Recent evidence has suggested that various cytokines are involved in the effects of abused drugs, suggesting that these factors play a role in drug dependence. In this article, the roles of glial cell line-derived neurotrophic factor (GDNF) and tumor necrosis factor-alpha (TNF-alpha) in drug dependence are discussed. GDNF inhibits the cocaine-induced upregulation of tyrosine hydroxylase activity in the ventral tegmental area and blocks behavioral responses to cocaine. TNF-alpha attenuates rewarding effects and locomotor sensitization induced by methamphetamine (METH) and morphine (MOR). Moreover, we mentioned the potential of Leu-Ile, which induces the expression of GDNF and TNF-alpha, as a novel therapeutic agent for drug dependence. Leu-Ile inhibits not only the development but also the maintenance of METH- or MOR-induced place preference and locomotor sensitization in mice. The inhibitory effect of Leu-Ile on METH- or MOR-induced place preference is not observed in GDNF heterozygous and TNF-alpha knockout mice. Leu-Ile inhibits METH- or MOR-induced place preference and sensitization by attenuating the METH- or MOR-induced increase in extracellular dopamine levels in the nucleus accumbens via the induction of GDNF and TNF-alpha expression. These findings suggest that Leu-Ile could be a novel therapeutic agent for drug dependence.

Involvement of glial cell line-derived neurotrophic factor in inhibitory effects of a hydrophobic dipeptide Leu-Ile on morphine-induced sensitization and rewarding effects.

There are few efficacious medications for drug dependence at present. We have previously demonstrated that Leu-Ile, which induces the expression of not only tumor necrosis factor-alpha (TNF-alpha) but also glial cell line-derived neurotrophic factor (GDNF), inhibits methamphetamine (METH) and morphine (MOR)-induced sensitization and rewarding effects by regulating extracellular dopamine levels via the induction of TNF-alpha expression, and indicated the potential of Leu-Ile as a novel therapeutic agent for METH and MOR-induced dependence. In the present study, we investigated the involvement of GDNF in inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects. Repeated treatment with MOR for 9 days, which results in an enhancement of the locomotor-stimulating effects (sensitization) of MOR, increased GDNF levels in the nucleus accumbens compared with those in saline-treated mice. Repeated pre-treatment with Leu-Ile for 9 days potentiated the MOR-induced increase in GDNF levels. MOR at a low dose (3mg/kg) produced place preference in GDNF heterozygous knockout (GDNF-(+/-)) mice, but not in littermate GDNF-(+/+) mice. No inhibitory effect of Leu-Ile on MOR-induced place preference was observed in GDNF-(+/-) mice. These results suggest that GDNF is involved in the inhibitory effects of Leu-Ile on MOR-induced sensitization and rewarding effects.

Enteric nervous system and developmental abnormalities in childhood.

ENS consists of a complex network of neurons, organised in several plexuses, which interact by means of numerous neurotransmitters. It is capable of modulating the intestinal motility, exocrine and endocrine secretions, microcirculation and immune and inflammatory responses within the gastrointestinal tract, independent of the central nervous system. Though the embryological development of various plexuses are completed by mid-way of gestation, the maturation of neurons and nerve plexuses appear to continue well after birth. Therefore, any histological or functional abnormalities related to the gastrointestinal function must be investigated with the ongoing maturational processes in mind.